From naive pluripotent stem cells to neuron progenitors: A study of the central gene regulatory networks in human

Abstract

Parkinson's disease is one of the most common neurodegenerative diseases, and stem cell therapy can be used to reduce patient's symptoms. In this therapy, dopamine producing neurons are transplanted into the patient's brain, after being derived from pluripotent stem cells (PSCs). To understand current protocols for this process and to find new ones, it is necessary to understand the gene regulatory mechanisms that drive it.
Therefore, two crucial parts of this process are modelled in this work.
First, a comprehensive, literature based model of the gene regulation behind different states of PSCs and their differentiation is presented and examined. Five major pathways are found to be most important for the maintenance of the primed and the naive state and the transition between them. Also, the core genes that maintain pluripotency by opposing differentiation and their interactions are identified.
Second, a simple gene regulatory model for neural patterning is presented and optimised towards data from in vitro neural patterning studies of induced PSCs. The optimised model is then validated by simulating the patterning of the neural tube during early brain development in vivo.
Both models deliver convincing results in their respective areas and enable new insights into the gene regulatory mechanisms that steer PSCs towards dopamine producing neurons.

Popular Abstract

How to make nerves from stem cells to fight Parkinson's disease

Parkinson's disease is one of the most common neural diseases for elderly people. Recent studies in stem cell research now hint that there is a new, efficient and potentially cheap method for the treatment of Parkinson's disease.

The brain does not age well - like an abandoned house. As we get older, it erodes. Parts of the brain will get brittle over time and they will eventually collapse. Unlike with a house, collapsed areas of the brain can not be rebuilt, so it is imperative to prevent damage from occurring or else one will get diseases like Alzheimer's - or Parkinson's disease.

In Parkinson's disease the patients symptoms - the most prominent of which is the uncontrollable shaking of the hands - are caused by a lack of the chemical dopamine in the brain. Dopamine helps the nerve cells in the brain to transmit signals and can be seen as the mortar, that holds the bricks of the brain together. In a healthy brain there are nerve cells that produce dopamine and supply it to the cells that need it; in the brain of a Parkinson's disease patient, the dopamine producing cells have died. This damages the dopamine dependent cells and eventually results in the collapse of brain regions - just like a brick wall without mortar would.

To prevent this from happening, the brains source of dopamine has to be restored, which can be done by transplanting dopamine generating cells into the patients brain.
A current strategy for that involves the use of stem cells - cells that can become any cell of the body. The stem cells are generated from cells taken from the patient for example by taking a small amount of skin. Then, the stem cells are put into a so called cocktail - a specific mixture of different hormones, proteins and other molecules - that makes the stem cells become nerves. Just before the new nerve cells are fully developed, they are transplanted into the patients brain, where they finalise their development and start producing dopamine.

Recently it has been found, that stem cells exist in different states and that controlling in which state a stem cell is can be utilised to simplify the process of making nerves out of stem cells and to make it significantly more efficient.

That would of course reduce the cost of Parkinson's disease treatment and therefore lead to better accessibility of therapies. Then already patients with weak Parkinson's disease symptoms could be treated with stem cell therapy, ensuring that the mortar in their brains does not vanish and that it stays stable for a longer time.

• author: Brambach, Max
• supervisor: Victor Olariu
• organization: Department of Astronomy and Theoretical Physics - Undergoing reorganization
• course: FYTM03 20181
• year: 2018
• type: H2 - Master's Degree (Two Years)
• subject: Physics and Astronomy
• keywords: Stem Cells, Neural Patterning, Naive State, Primed State, Ground State, Systems Biology, Embryonic Development, Gene Regulation
• language: English
• id: 8945230
• date added to LUP: 2018-06-08 08:51:36
• date last changed: 2018-06-08 08:51:36